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1.
Acta Pharmacol Sin ; 29(11): 1357-69, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18954531

RESUMO

AIM: To determine the in vitro and in vivo bioactivity of recombinant human endostatin (rhEndostatin) and to analyze its pharmacokinetics and immunogenicity in rhesus monkeys and patients. METHODS: The physical chemical characteristics of rhEndostatin were detected according to Pharmacopoeia of the People's Republic of China (2005 edition, part III). Its in vitro and in vivo bioactivities were assayed via proliferation-inhibition on human umbilical vein endothelial cells and their inhibitory effect on tumor-bearing mice models. Serum concentrations of rhEndostatin in monkeys and patients were determined by an enzyme immunoassay method. RESULTS: The corresponding specific in vitro activities of rhEndostatin obtained from the cell counting method, 3-(4,5-dimethylthiazol-2- yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and lactate dehydrogenase assay, respectively, were 6.4 x 10(7), 6.7 x 10(7), and 3.8 x 10(8) U/mg, and the in vivo antitumoral potency was 4.04 x 10(7) U/mg. In rhesus monkeys, there were no gender differences in all pharmacokinetic parameters. Serum anti-rhEndostatin immunoglobulin (Ig)G antibodies were generated quickly after intravenous (iv) administration and decreased rapidly when therapy was stopped. In phase I clinical trials, linearity in the pharmacokinetics of rhEndostatin was indicated by dose-proportionate increases in the area under the curve and the maximum serum concentration. Serum rhEndostatin reached a steady-state level after 7 d of successive administration with the average concentration at a steady state of 272.44+/-91.98 ng/mL. Neither IgG nor IgM antibodies against rhEndostatin were observed in patients. CONCLUSION: RhEndostatin exhibited a definite proliferation- inhibition effect on HUVEC, and significant antitumoral activity in mice. The immunoreactivity of rhesus monkeys to rhEndostatin is common, and rhEndostatin showed no immunogenicity in patients in this trial. The results provide a basis for further clinical trials.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/uso terapêutico , Endostatinas/uso terapêutico , Inibidores da Angiogênese/imunologia , Inibidores da Angiogênese/farmacocinética , Animais , Antineoplásicos/imunologia , Antineoplásicos/farmacocinética , Endostatinas/imunologia , Endostatinas/farmacocinética , Células Endoteliais/efeitos dos fármacos , Feminino , Humanos , Macaca mulatta , Masculino , Camundongos , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/uso terapêutico , Caracteres Sexuais , Sais de Tetrazólio , Tiazóis
2.
Eur J Pharmacol ; 564(1-3): 1-6, 2007 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-17346697

RESUMO

Recombinant human endostatin (rhEndostatin) has been shown to inhibit tumor growth, but the variable antitumor activity of different rhEndostatin preparations has necessitated the development of an accurate, reproducible in vivo bioassay for evaluating the rhEndostatin activity. To assess the in vivo antitumor efficacy of rhEndostatin, H22 tumor-bearing mice received three doses of rhEndostatin and the potency of rhEndostatin preparations in inhibiting tumor growth was determined by ED(50)-potency assay and validated by dose-response parallel-line assay. There was a consistent and highly reproducible linear regression relationship between rhEndostatin dosage and tumor growth inhibition rate. The ED(50) values were determined from dose-response regression lines for seven rhEndostatin preparations with high reproducibility. On the basis of the current study, the potency of rhEndostatin preparations was assigned a value of 6.09 x 10(5) U/ampoule and a 95% confidence limit of 5.96 x 10(5)-6.22 x 10(5). We consider that this procedure can be served as a potential candidate pharmacopoeial method for potency measurement of different rhEndostatin preparations.


Assuntos
Antineoplásicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Endostatinas/farmacologia , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Análise de Variância , Animais , Antineoplásicos/administração & dosagem , Intervalos de Confiança , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Endostatinas/administração & dosagem , Humanos , Modelos Lineares , Masculino , Camundongos , Farmacopeias como Assunto , Distribuição Aleatória , Reprodutibilidade dos Testes
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